The Drug Hunters

by Donald R Kirsch

  Another ancient drug that is still in use today is digitalis, which remains the drug of choice for many cardiac patients. Plant extracts containing digitalis compounds were used in primitive societies as arrow poisons. One of the first digitalis drugs is mentioned in the Ebers Papyrus, a document containing Egyptian herbal knowledge written around 1550 BC, which means the Egyptians were using the plant extract more than 3,500 years ago. Digitalis is also mentioned in writings by Welsh physicians from 1250 AD. The plant from which digitalis is extracted, foxglove, was described botanically by Fuchsius in 1542 who named it Digitalis purpea based on the appearance of the flower, which is purple in color and is said to resemble a human finger.

  The therapeutic value of digitalis was fully described by the physician William Withering in a 1785 book entitled An Account of the Foxglove and Some of Its Medical Uses: with Practical Remarks on Dropsy and Other Diseases. Withering described how he first came to use digitalis some ten years prior to the publication of his treatise:

  In the year 1775, my opinion was asked concerning a family in receipt of the cure of the dropsy. I was told that it had long been kept a secret by an old woman in Shropshire, who had sometimes made cures after the more regular practitioners had failed. I was informed also, that the effects produced were violent vomiting and purging: for the diuretic effects seem to have been overlooked. This medicine was composed of twenty or more different herbs: but it was not very difficult for one conversant in these subjects, to perceive, that the active herb could be none other than the Foxglove.

  Dropsy is an archaic term for the swelling of soft tissues due to the accumulation of excess water, today called edema. It is commonly seen in heart failure. Withering was an expert botanist as well as a physician, which enabled him to recognize that foxglove was likely the active ingredient in the complex mixture promoted by the Shropshire woman. Even so, Withering did not appreciate that the primary benefits of foxglove were due to its actions on the heart, though he did recognize that foxglove produced cardiac effects, writing:

  It has a power over the motion of the heart to a degree unobserved in any other medicine, and this power may be converted to salutary ends.

  Despite Withering’s clear description of both the benefits and harmful side effects of foxglove, the drug was used indiscriminately throughout the nineteenth century for a wide variety of diseases, often in doses that were toxic. During the early twentieth century, the drug came to be used specifically for atrial fibrillation (an irregular and rapid heart rate) and in the middle of the twentieth century it was finally appreciated that the main therapeutic value of digitalis is as a treatment for congestive heart failure. A damaged heart muscle will work more efficiently in the presence of digitalis, restoring the health of a patient following a heart attack. In order to achieve this effect, digitalis must be dosed with great precision, as even a slight overdose will make the patient’s condition worse rather than better.

  One final drug that was used during ancient times and that still has modern value is colchicine, a treatment for gout. Gout is a painful inflammatory disease that results from the deposit of uric acid crystals in the joints, most commonly in the joints of the large toe. Ancient Egyptians first described gout in 2,600 BC as a kind of arthritis of the big toe. It was often referred to as a “rich man’s disease,” because there is a strong association between gout and the consumption of alcohol, sugary drinks, meat, and seafood, foods that were once limited to the wealthy classes. An English physician named Thomas Sydenham penned an early description of the disease in 1683:

  Gouty patients are, generally, either old men, or men who have so worn themselves out in youth as to have brought on a premature old age—of such dissolute habits none being more common than the premature and excessive indulgence in venery, and the like exhausting passions. The victim goes to bed and sleeps in good health. About two o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. The pain is like that of a dislocation, and yet parts feel as if cold water were poured over them. Then follows chills and shivers, and a little fever…. The night is passed in torture, sleeplessness, turning the part affected, and perpetual change of posture; the tossing about of body being as incessant as the pain of the tortured joint, and being worse as the fit comes on.

  Many modern treatments for gout focus on eliminating the uric acid crystals that cause the painful symptoms. Since gout is an inflammatory disease, anti-inflammatory drugs are often effective in relieving its symptoms, such as ibuprofen. Colchicine is extracted from the seeds and tuber of Colchicum automnale, also known as the autumn crocus or meadow saffron. Colchicum plant material was recommended for the treatment of rheumatism and swelling in the Ebers Papyrus, and for the treatment of gout by Greek physician Alexander of Tralles in the middle of the fifth century AD. Benjamin Franklin suffered from gout and is said to have been responsible for introducing colchicum to the American colonies. Interestingly, since cochicine has been used for so very long, no one ever bothered to seek Food and Drug Administration approval for it as a stand-alone gout treatment until 2009, about 3,500 years after its clinical introduction.

  20: Dover’s Powder: In 1709, Dover’s expedition landed at a deserted island off the coast of Chile that was part of the Juan Fernandez archipelago. There they found Alexander Selkirk, a man from Largo, Scotland, who had escaped to sea to in 1703 in order to avoid a command to appear in court for “undecent carriage” (indecent behavior) in church. Selkirk had sailed from England on the privateer Cinque Ports but abandoned the ship for the remote island in 1704 following a dispute over the vessel’s seaworthiness. Indeed, the Cinque Ports later foundered, losing most of its hands. Selkirk was wise to get off the ship, but even so, he was stranded for more than four years until his rescue by Dover’s expedition. Selkirk became a minor celebrity in England with his story being recounted in a much-read article that appeared in the magazine, “The Englishman,” eventually inspiring Daniel Defoe to write Robinson Crusoe.

  Chapter 2: Countess Chinchón’s Cure: The Library of Botanical Medicine

  37: A year after Talbor’s death: Today, most problems of drug misrepresentation occur around issues pertaining to off-label promotion—marketing drugs for uses not approved of by the FDA—or from pharma companies providing kickbacks to physicians as compensation for prescribing the company’s drugs. Recent lawsuits that involved off-label promotion have included a $2.2 billion legal settlement by Johnson and Johnson in 2013, a $3 billion settlement by Glaxo Smithkline in 2012 (of which $1 billion was for criminal charges), and a $2.3 billion Pfizer settlement in 2009.

  Chapter 3: Standard Oil and Standard Ether: The Library of Industrial Medicine

  44: Dr. John Warren, one of the founders of Harvard Medical School: John Warren was born in Roxbury, Massachusetts, near Boston on July 27, 1753. He was the youngest of four brothers. His father, also Joseph Warren, was an apple farmer and Calvinist who strongly instilled within his sons the value of higher education and love of country. John, Jr. did well in grammar school and attended Harvard, entering in 1767 at the ripe age of fourteen years. At Harvard he learned Latin, became a competent classical scholar, and developed a strong interest in the study of anatomy, joining the Anatomical Club, where he dissected lower animals and studied the human skeleton. Studying human bones was not easy, as there was no ready supply of corpses. In order to pursue his studies, Warren along with his fellow students kept a close watch on the disposal of dead criminals and vagrants.

  After graduation, Warren started a medical practice in Salem, Massachusetts, in 1773. Warren’s practice was greatly affected by the Revolutionary War, and his brother Joseph was killed during the battle of Bunker Hill. In 1780, John Warren was among the first to propose the establishment of a medical school as part of Harvard University. By 1782, Harvard had established three professorships in medicine, and Warren was appointed chairman of the anatomy department at the new medical school.

 
One of his students, James Jackson, wrote that one of the “most peculiar charms” of Warren’s teaching was “derived from the animation of delivery, from the interest he displayed in the subject of his discourse and from his solicitude that every auditor be satisfied both by his demonstrations and by his explanations.” Warren developed a reputation as an excellent surgeon, highly regarded for pioneering new surgical procedures. By 1815, Harvard Medical School had fifty students, and John Warren’s oldest son, John Collins Warren, served as adjunct professor in anatomy and surgery. Thirty years after that, this adjunct professor performed the very first operation conducted under anesthesia.

  Chapter 4: Indigo, Crimson, and Violet: The Library of Synthetic Medicine

  67: Salicylates had been used for thousands of years: Most plants produce salicylates, which are hormones that enable different parts of the plant to communicate with each other. The willow tree happens to be a particularly rich source of these compounds but is otherwise unremarkable in salicylate physiology. An example of the operation of salicylates can be seen when a plant is afflicted with a disease known as systemic acquired resistance (SAR), a condition that occurs when one part of the plant is infected by a virus or fungus. If you try to infect a different part of the plant with the same pathogen a day or two after the initial infection, the plant will now be resistant to the pathogen. Why? The infected part of the plant releases salicylates into its vascular system, where it circulates to other parts of the plant and triggers the production of toxins that are kind of like plant antibodies (known as resistance factors) at these new sites, which help control the spread of the infection.

  Plant resistance factors can be very toxic and can even cause an entire part of a plant to die off; this is not a defense strategy that can be used by animals, as losing an arm or leg is likely a worse state of affairs than dealing with a disease. But since a plant can survive the loss of one of its branches or roots, it is an excellent survival strategy for flora. This is why you often see a tree or bush with a dead limb. Animals on the other hand, including humans, possess an analogous defense system called innate immunity. One of the reasons we feel so crappy when we are sick with a cold or the flu is that our innate immunity system has kicked in and is producing chemicals that are toxic to the pathogen—but also toxic to ourselves.

  70: Their antibiotic eventually received FDA approval and is currently generating over $1 billion in annual sales: Another example of a poor decision to cut bait instead of continuing to fish can be found in the hunt for anticholesterol drugs. In 1975, driven by new discoveries in biochemistry, Merck stepped up its efforts to study the synthesis of cholesterol in the body. It was known that HMG-CoA reductase was the first enzyme in the body’s pathway for synthesizing cholesterol, and so Merck scientists began to search for compounds that inhibited HMG-CoA reductase. They speculated that such inhibitors might prove to be effective anticholesterol drugs. After just one week of testing a few hundred random samples, the researchers detected a very strong HMG-CoA reductase inhibitor candidate. This was an exceptionally speedy triumph, since it commonly takes several thousands of samples to find a good candidate. In 1979, the Merck scientist Carl Hoffman purified the inhibiting compound, giving rise to one of the earliest successful statin drugs, lovastatin. The drug was approved by the FDA in 1987 as a standard treatment for hypercholesterolemia.

  At this point, Merck had a head start on other drug companies in the search for other viable anticholesterol drugs. Since lovastatin came from a soil microorganism, Merck reasoned that the library of dirt was the best place to find better statin drugs, even though they had already made progress in searching the library of synthetic molecules for HMG-CoA inhibitors. Merck decided to cut bait and curtail their efforts to develop a better anticholesterol medication through synthetic chemistry and instead focus solely on soil-based compounds.

  Sensing opportunity, Merck’s competitor Warner Lambert picked up on the chemistry line of HMG-CoA inhibitor research that Merck had abandoned and discovered an even better inhibitor—Lipitor. Lipitor quickly and dramatically outpaced the sales of lovastatin (and another one of Merck’s soil-based statin drugs, simvistatin).

  Chapter 6: Medicine That Kills: The Tragic Birth of Drug Regulation

  98: Bayer dubbed their new drug Prontosil: Even though the discovery of Prontosil was based on a totally false hypothesis (the notion that dyes could be effective antimicrobial drugs), there was no arguing with its success. Gerhard Domagk, the Bayer research director who led the Prontosil research team, was awarded the 1939 Nobel Prize in Medicine. Unfortunately for Domagk, he did not get to enjoy his prize for long. The earlier award of the 1935 Nobel Peace Prize to Carl von Ossietzky, a German who was very critical of the Nazis, had so angered the German government that the Nazis made it illegal for any German to accept a Nobel Prize. Domagk was forced by the Nazi regime to refuse the prize, and he was eventually arrested by the Gestapo and jailed for a week.

  105: the Food and Drug Administration oversees the development of drugs from the very beginning: Regulatory authorities have avoided providing a defined checklist of required experiments for clinical testing and instead issue general guidance notes for the required studies. Despite the reluctance of the FDA to share explicit guidelines, in practice the required studies are easily described via a checklist:

  • Testing for Acute Toxicity: The drug is administered to a laboratory animal, usually a rodent, in increasing doses and the animal is observed for toxic effects following each dose. The dose range is large; from very low doses to the highest well-tolerated level (called the “no toxic effect level”) and up to higher doses that produce obvious toxicity. At the end of each experiment, the animals are sacrificed and autopsied to search for any effects the drug may have had on their internal organs.

  • Testing for QT Interval Prolongation: It is well known that some pharmaceutical targets can be very difficult to inhibit, some are relatively easy to inhibit, and some are so susceptible to the influence of drugs that they are sometimes unintentionally inhibited by drugs designed to act elsewhere. One of these highly susceptible targets is the cardiac hERG channel, an ion channel involved in regulating the rhythmic action of the heart. Inhibition of the hERG channel causes prolongation of the QT interval in the heart rhythm, which can lead to a potentially fatal heart arrhythmia called torsades de pointes. Drugs from many different therapeutic classes, including tricyclic antidepressants, antipsychotics, antihistamines, and antimalarials, all inhibit the hERG channel. hERG channel inhibition must therefore be measured prior to the initiation of clinical trials.

  • Testing for Genotoxicity: Cancer is caused by gene mutations that can either be inherited or produced during the course of life by exposure to certain viruses, radiation, or mutagenic chemicals. It is therefore crucial to avoid producing drugs that have any mutagenic activity, as such drugs could be carcinogenic. Bruce Ames, one of the scientists responsible for our current understanding of the mutagenic nature of carcinogenesis, developed a straightforward bacterial-based test, named the Ames test in his honor, to detect mutagenic activity and thus carcinogenic potential in any chemical compound. The FDA requires Ames testing as part of NDA testing, as well as related tests for chromosomal abnormalities and chromosomal damage in rodents.

  • Testing for Chronic Toxicology: The acute toxicity study looks for immediate damage produced by a drug. However, there is also the concern that toxicity may occur when the drug is dosed repeatedly over time, even at low doses. Chronic toxicology studies address this concern. Three (or more) doses of a particular drug are administered over an extended period of time: a dose known to be toxic (from the acute toxicity study), a therapeutic dose, and an intermediary dose. This test is carried out on two species: a rodent (usually rats) and a non-rodent (usually dogs, though monkeys and pigs are used in certain circumstances). The duration of the chronic toxicity trial must match the intended clinical use. A two-week trial is adequate for a compound like an antibiotic that will be
administered only for a few days. Studies of six months or more in duration are required for drugs that will be chronically administered, such as high blood pressure medications. Such studies can obviously be extraordinarily expensive because they must be conducted over a long period of time and require a large number of animals (100 rats and 20 dogs would be typical); in addition, the test requires large amounts of the actual test drug, which must be prepared in a costly fashion in order to meet the exacting FDA standards.

  The reason it is so expensive to manufacture drugs for FDA testing is that they must be prepared under “good manufacturing practices” (GMP) guidelines. The synthetic process must be clearly defined and described in detail and followed precisely from batch to batch. Analytical procedures must be developed and validated to ensure quality control of the manufactured drug. The purity of the drug must be determined, and any impurities present must be defined, characterized, and rendered consistent from batch to batch. In addition, the drugs are not just administered to test subjects in a straightforward manner, but are dosed in a complex formulation that optimizes the delivery of the drug. This formulation must be optimized and remain fixed for all future studies. Finally, these studies must be carried out in specialized GMP laboratories operated under close regulatory oversight.